Is FREM2 p.Ser2867Phe (c.8600C>T) pathogenic?

FREM2 p.Ser2867Phe (c.8600C>T) is classified Uncertain significance in FREM2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-14). AlphaMissense: ambiguous (0.4634); Ultra-rare (popmax 0.012%, afr); Associated with Fraser syndrome 2.

What condition is associated with FREM2 p.Ser2867Phe (c.8600C>T)?

FREM2 p.Ser2867Phe (c.8600C>T) is associated with Fraser syndrome 2, isolated cryptophthalmia (ClinVar).

How common is FREM2 p.Ser2867Phe (c.8600C>T) in the general population?

FREM2 p.Ser2867Phe (c.8600C>T) is ultra-rare (popmax 0.012%, afr) (gnomAD).

What do computational predictors say about FREM2 p.Ser2867Phe (c.8600C>T)?

AlphaMissense predicts ambiguous (score 0.4634) — an in-silico prediction, not a clinical call.

FREM2 p.Ser2867Phe

c.8600C>T · rs141835500 · VCV2254856

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4634 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.012%, afr)

Conditions

Fraser syndrome 2

Computational evidence

Protein change
AlphaMissense	0.4634	ambiguous
REVEL	0.601	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.8, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 25 kb · p 0.00037 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.012% African / African-American · 9/74,906 alleles

Filtering AF 0.00624% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00468%

Overall 0.000682% 11/1,613,924 alleles · ultra-rare exomes 5/1,461,750 · genomes 6/152,174 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.012%	8,323
Admixed American	0.00167%	59,994
Remaining individualsnot grpmax-eligible	0.0016%	62,488

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FREM2
Protein: p.Ser2867Phe
Coding: c.8600C>T
MANE Select: NM_207361
dbSNP: rs141835500
Type: single nucleotide variant
Location: chr13:38877172 (GRCh38)
Gene constraint: LOEUF 0.588 · pLI <0.01 (gnomAD)
Residue 2867: a UniProt-annotated variant site (in cryptop)

Full FREM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Fraser syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: isolated cryptophthalmia

Similar variants

FREM2 p.Arg1355Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Arg638Ter Likely pathogenic ★★ same condition
FREM2 p.Arg736Ter Pathogenic ★★ same condition
FREM2 p.Arg809Ter Pathogenic ★★ same condition
FREM2 p.Gln1051Ter Pathogenic/Likely pathogenic ★★ same condition
FREM2 p.Gln717Ter Likely pathogenic ★★ same condition
FREM2 p.Ala1659Thr Uncertain significance ★★ ⚠ same condition
FREM2 p.Ala1664Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/frem2-p-ser2867phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown